The therapeutic effect of creatine on HD will be studied under this grant. There is no FDA-approved treatment for HD, and a therapeutic strategy to impact either directly or indirectly on the neurodegenerative processes causing HD is still missing. The National Institutes of Health estimates an HD prevalence of about 1 in every 10,000 people in the US. This grant would support a multicenter, Phase 3 trial to study the effect of creatine on HD, using standard clinical HD measures. In a double-blind, placebo-controlled study of 8 g/d creatine for 16 weeks, the investigator's group demonstrated that creatine, in addition to being safe and tolerable, increased serum and brain levels of creatine and markedly reduced a serum marker of oxidative injury to DNA suggesting beneficial effects on a fundamental mechanism of pathogenesis in HD. They examined higher doses of creatine in early symptomatic subjects, and the data have provided evidence for a higher optimal dose with greater suppression of oxidative injury and evidence for a reduction in progressive brain atrophy. Creatine is a strong candidate for treating HD. There are several mechanisms by which creatine may be neuroprotective: (1) it may provide an energy buffer for neurons, helping them maintain their transmembrane potential and calcium homeostasis, the loss of either of which leads to neuronal dysfunction and death;(2) phosphocreatine regenerates ATP in the cytoplasm that is then utilized by the sodium potassium ATPase to maintain membrane potential, and by calcium ATPase for calcium buffering. Impaired calcium buffering has been demonstrated in mice in which the creatine kinase system has been impaired. Intracellular calcium levels are known to be important in cell death in both cerebral ischemia as well as following excitotoxicity;(3) creatine enhances glutamate uptake and might thereby protect neurons from excitotoxicity;(4) creatine administration increases phosphocreatine in hippocampal slices, delays synaptic failure, and decreases hypoxic damage, and (5) creatine blocks the mitochondrial transition pore, a trigger for apoptotic cell death in neurons.